JP2009029805A - クロピドグレルの製造方法 - Google Patents
クロピドグレルの製造方法 Download PDFInfo
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- JP2009029805A JP2009029805A JP2008179540A JP2008179540A JP2009029805A JP 2009029805 A JP2009029805 A JP 2009029805A JP 2008179540 A JP2008179540 A JP 2008179540A JP 2008179540 A JP2008179540 A JP 2008179540A JP 2009029805 A JP2009029805 A JP 2009029805A
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- formula
- compound
- salt
- acid
- thieno
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 18
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 title description 16
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 title description 10
- 229960003009 clopidogrel Drugs 0.000 title description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 111
- 150000003839 salts Chemical class 0.000 claims abstract description 109
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 239000000376 reactant Substances 0.000 claims abstract description 25
- 230000003287 optical effect Effects 0.000 claims abstract description 17
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000002378 acidificating effect Effects 0.000 claims abstract 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 141
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 114
- 238000000034 method Methods 0.000 claims description 71
- 239000002904 solvent Substances 0.000 claims description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 70
- -1 methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c] pyrid-5-yl) Chemical group 0.000 claims description 69
- 239000000203 mixture Substances 0.000 claims description 53
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- 239000002253 acid Substances 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 31
- RSIAZRBSDZRPNS-UHFFFAOYSA-N n-[2-(2-chlorophenyl)-6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl]acetamide Chemical compound C=1C=2CN(NC(=O)C)CCC=2SC=1C1=CC=CC=C1Cl RSIAZRBSDZRPNS-UHFFFAOYSA-N 0.000 claims description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 26
- JFDVAYOTONCKQN-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetonitrile Chemical compound ClC1=CC=CC=C1C(C#N)N1CC(C=CS2)=C2CC1 JFDVAYOTONCKQN-UHFFFAOYSA-N 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 230000006340 racemization Effects 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- 150000007513 acids Chemical class 0.000 claims description 9
- 239000000460 chlorine Chemical group 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 229910052740 iodine Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000011975 tartaric acid Substances 0.000 claims description 5
- UWCWUCKPEYNDNV-LBPRGKRZSA-N 2,6-dimethyl-n-[[(2s)-pyrrolidin-2-yl]methyl]aniline Chemical compound CC1=CC=CC(C)=C1NC[C@H]1NCCC1 UWCWUCKPEYNDNV-LBPRGKRZSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229960001367 tartaric acid Drugs 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 3
- 229940106681 chloroacetic acid Drugs 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 235000010755 mineral Nutrition 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000012736 aqueous medium Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 3
- 229960001270 d- tartaric acid Drugs 0.000 claims 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical group C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims 1
- 229930007886 (R)-camphor Natural products 0.000 claims 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229960000846 camphor Drugs 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 claims 1
- 239000012433 hydrogen halide Substances 0.000 claims 1
- 229910000039 hydrogen halide Inorganic materials 0.000 claims 1
- 229940079826 hydrogen sulfite Drugs 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 235000019260 propionic acid Nutrition 0.000 claims 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- MKYRMMMSZSVIGD-UHFFFAOYSA-N thieno[3,2-c]pyridine Chemical class N1=CC=C2SC=CC2=C1 MKYRMMMSZSVIGD-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000047 product Substances 0.000 description 121
- 239000011541 reaction mixture Substances 0.000 description 67
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
- 239000000243 solution Substances 0.000 description 34
- 230000008018 melting Effects 0.000 description 29
- 238000002844 melting Methods 0.000 description 29
- 239000012044 organic layer Substances 0.000 description 29
- 238000002329 infrared spectrum Methods 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 23
- 238000001819 mass spectrum Methods 0.000 description 22
- 239000011734 sodium Substances 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 239000002244 precipitate Substances 0.000 description 19
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 14
- SRKXAUBVRPEIQR-CQSZACIVSA-N (2r)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetamide Chemical compound C1([C@@H](N2CC=3C=CSC=3CC2)C(=O)N)=CC=CC=C1Cl SRKXAUBVRPEIQR-CQSZACIVSA-N 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 12
- GKTWGGQPFAXNFI-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acid methyl ester Chemical compound C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl GKTWGGQPFAXNFI-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 9
- OGUWOLDNYOTRBO-UHFFFAOYSA-N 4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1NCCC2=C1C=CS2 OGUWOLDNYOTRBO-UHFFFAOYSA-N 0.000 description 8
- TYMOIAIKFNUQHY-UHFFFAOYSA-N [2-(2-chlorophenyl)-6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl] acetate Chemical compound C=1C=2CN(OC(=O)C)CCC=2SC=1C1=CC=CC=C1Cl TYMOIAIKFNUQHY-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 230000000704 physical effect Effects 0.000 description 8
- SRKXAUBVRPEIQR-AWEZNQCLSA-N (2s)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetamide Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)N)=CC=CC=C1Cl SRKXAUBVRPEIQR-AWEZNQCLSA-N 0.000 description 7
- FDEODCTUSIWGLK-UHFFFAOYSA-N hydrogen sulfate;hydron;methyl 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate Chemical compound OS(O)(=O)=O.C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl FDEODCTUSIWGLK-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- GAQWDBUWBUOFLS-DLGLCQKISA-N [(4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid;hydrate Chemical compound O.C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C GAQWDBUWBUOFLS-DLGLCQKISA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- FDEODCTUSIWGLK-RSAXXLAASA-N clopidogrel sulfate Chemical compound [H+].OS([O-])(=O)=O.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl FDEODCTUSIWGLK-RSAXXLAASA-N 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- GAQWDBUWBUOFLS-YZUKSGEXSA-N [(1r,4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid;hydrate Chemical compound O.C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C GAQWDBUWBUOFLS-YZUKSGEXSA-N 0.000 description 4
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 4
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 3
- SRKXAUBVRPEIQR-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetamide Chemical compound C1CC=2SC=CC=2CN1C(C(=O)N)C1=CC=CC=C1Cl SRKXAUBVRPEIQR-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- DCASRSISIKYPDD-UHFFFAOYSA-N clopidogrel carboxylic acid Chemical compound C1CC=2SC=CC=2CN1C(C(=O)O)C1=CC=CC=C1Cl DCASRSISIKYPDD-UHFFFAOYSA-N 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- 239000003586 protic polar solvent Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-Phenylalanine Natural products OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000007059 Strecker synthesis reaction Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 229910052736 halogen Chemical group 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DCASRSISIKYPDD-CQSZACIVSA-N (2r)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-ium-5-yl)acetate Chemical compound C1([C@@H](N2CC=3C=CSC=3CC2)C(=O)O)=CC=CC=C1Cl DCASRSISIKYPDD-CQSZACIVSA-N 0.000 description 1
- JFDVAYOTONCKQN-AWEZNQCLSA-N (2r)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetonitrile Chemical compound ClC1=CC=CC=C1[C@H](C#N)N1CC(C=CS2)=C2CC1 JFDVAYOTONCKQN-AWEZNQCLSA-N 0.000 description 1
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 1
- 0 *C(c1ccccc1)N(CC1)Cc2c1[s]cc2 Chemical compound *C(c1ccccc1)N(CC1)Cc2c1[s]cc2 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000694440 Colpidium aqueous Species 0.000 description 1
- ZZEFPEHHYIUBHO-UHFFFAOYSA-N NC(C(c1ccccc1)N(CC1)Cc2c1[s]cc2)=O Chemical compound NC(C(c1ccccc1)N(CC1)Cc2c1[s]cc2)=O ZZEFPEHHYIUBHO-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- CWXRDRRRMYZKJX-UHFFFAOYSA-N [2-(2-chlorophenyl)-6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl] acetate;sulfuric acid Chemical compound OS(O)(=O)=O.C=1C=2CN(OC(=O)C)CCC=2SC=1C1=CC=CC=C1Cl CWXRDRRRMYZKJX-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- UPNDWBGAHULZEO-UHFFFAOYSA-N acetamide (7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]heptanyl)methanesulfonic acid Chemical compound C12(C(=O)CC(CC1)C2(C)C)CS(=O)(=O)O.C(C)(=O)N UPNDWBGAHULZEO-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- PZAGQUOSOTUKEC-UHFFFAOYSA-N acetic acid;sulfuric acid Chemical compound CC(O)=O.OS(O)(=O)=O PZAGQUOSOTUKEC-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000004972 metal peroxides Chemical class 0.000 description 1
- GKTWGGQPFAXNFI-OAHLLOKOSA-N methyl (2r)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate Chemical compound C1([C@@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-OAHLLOKOSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000007122 ortho-metalation reaction Methods 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 150000002910 rare earth metals Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN84MU2001 IN191030B (es) | 2001-01-24 | 2001-01-24 | |
| US10/054,101 US6635763B2 (en) | 2001-01-24 | 2001-10-22 | Process to prepare clopidogrel |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002559430A Division JP5000841B2 (ja) | 2001-01-24 | 2002-01-21 | クロピドグレルの製造方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2009029805A true JP2009029805A (ja) | 2009-02-12 |
Family
ID=11097211
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008179540A Withdrawn JP2009029805A (ja) | 2001-01-24 | 2008-07-09 | クロピドグレルの製造方法 |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US6635763B2 (es) |
| JP (1) | JP2009029805A (es) |
| KR (1) | KR100632748B1 (es) |
| IN (1) | IN191030B (es) |
| PT (1) | PT1353928E (es) |
| ZA (1) | ZA200304895B (es) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2363053C (en) * | 2001-11-09 | 2011-01-25 | Bernard Charles Sherman | Clopidogrel bisulfate tablet formulation |
| US7074928B2 (en) | 2002-01-11 | 2006-07-11 | Teva Pharmaceutical Industries, Ltd. | Polymorphs of clopidogrel hydrogensulfate |
| US6800759B2 (en) | 2002-08-02 | 2004-10-05 | Teva Pharmaceutical Industries Ltd. | Racemization and enantiomer separation of clopidogrel |
| IL166593A0 (en) | 2002-08-02 | 2006-01-15 | Racemization and enantiomer separation of clopidogrel | |
| AU2003238664A1 (en) | 2003-03-12 | 2004-09-30 | Cadila Healthcare Limited | Polymorphs and amorphous form of (s) - (+) -clopidogrel bisulfate |
| DK1618111T3 (en) | 2003-04-25 | 2015-02-16 | Cadila Healthcare Ltd | Salts of clopidogrel and the process for preparing |
| US20050059696A1 (en) * | 2003-05-08 | 2005-03-17 | Dr. Reddy's Laboratories Limited | Process for the recovery of S -(+)-methyl- (2-chlorophenyl)- (6,7-dihydro- 4H-thieno [3,2-c] pyrid-5-yl) acetate hydrogen sulfate (clopidogrel bisulfate) from its (R) and mixture of (R) and (S)- isomers |
| ES2339944T3 (es) | 2003-11-03 | 2010-05-27 | Cadila Healthcare Limited | Procedimientos para preparar la forma i de bisulfato de (s)-(+)-clopidogrel. |
| CA2457459A1 (en) * | 2004-02-11 | 2005-08-11 | Brantford Chemicals Inc. | Resolution of racemates of methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)-(2-chlorophenyl) acetate |
| EP1772455A3 (en) * | 2004-03-05 | 2007-06-27 | IPCA Laboratories Limited | Industrial process for preparation a polmorph of clopidogrel hydrogen sulphate |
| KR100563455B1 (ko) * | 2004-04-09 | 2006-03-23 | 한미약품 주식회사 | 결정성 클로피도그렐 나프탈렌술폰산염 또는 이의 수화물,이의 제조방법 및 이를 함유하는 약학적 조성물 |
| KR100681512B1 (ko) * | 2005-03-08 | 2007-02-09 | 주식회사 한서켐 | 클로피도그렐의 신규한 제조 중간체 및 이를 이용한 클로피도그렐의 제조방법 |
| KR20080008403A (ko) * | 2005-05-10 | 2008-01-23 | 엘란 파마 인터내셔널 리미티드 | 나노입자형 클로피도그렐 제제 |
| US20070003615A1 (en) * | 2005-06-13 | 2007-01-04 | Elan Pharma International Limited | Nanoparticulate clopidogrel and aspirin combination formulations |
| KR100678287B1 (ko) * | 2005-06-23 | 2007-02-02 | 한미약품 주식회사 | 클로피도그렐의 제조방법 및 이에 사용되는 중간체 |
| ES2391410T3 (es) | 2005-09-05 | 2012-11-26 | Cadila Healthcare Limited | Procedimientos para la preparación de diferentes formas de (s)-(+)-clopidogrel besilato |
| KR20070066518A (ko) * | 2005-12-22 | 2007-06-27 | 에스케이케미칼주식회사 | 고체상 반응을 이용한 (ｓ)-(＋)-클로피도그렐의 제조방법 |
| KR101235117B1 (ko) * | 2005-12-26 | 2013-02-20 | 에스케이케미칼주식회사 | 광학분리에 의한 (ｓ)-(＋)-클로피도그렐의 제조방법 |
| US20070191609A1 (en) * | 2006-02-13 | 2007-08-16 | Lee Pharma Limited | Process for preparation of clopidogrel bisulphate form-1 |
| WO2008019053A2 (en) * | 2006-08-03 | 2008-02-14 | Teva Pharmaceutical Industries Ltd. | Process for preparing clopidogrel bisulphate |
| DE602007012121D1 (de) * | 2006-09-04 | 2011-03-03 | Ranbaxy Lab Ltd | Verbessertes verfahren zur herstellung von clopidogrel und pharmazeutisch unbedenklichen salzen davon |
| WO2008081473A2 (en) * | 2006-12-29 | 2008-07-10 | Cadila Healthcare Limited | Process for preparing clopidogrel |
| MX2008016012A (es) * | 2007-04-18 | 2009-03-06 | Teva Pharma | Proceso mejorado para preparar clopidogrel. |
| EP2346879A1 (en) * | 2008-10-24 | 2011-07-27 | Sandoz AG | A process for the preparation of s-clopidogrel |
| CN101695496A (zh) * | 2009-10-15 | 2010-04-21 | 苏春华 | 一种含有三氟柳和氯吡格雷的药物组合物 |
| WO2012123958A1 (en) | 2011-02-14 | 2012-09-20 | Cadila Healthcare Limited | Highly pure salts of clopidogrel free of genotoxic impurities |
| US20230059869A1 (en) | 2021-08-03 | 2023-02-23 | Liqmeds Worldwide Limited | Oral pharmaceutical solution of clopidogrel |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63203684A (ja) * | 1987-02-17 | 1988-08-23 | サノフイ | 右旋性α−５−（４，５，６，７−テトラヒドロ［３，２−ｃ］チエノピリジル）−（２−クロロフェニル）酢酸メチル、その製法および医薬 |
| JP2004522744A (ja) * | 2001-01-24 | 2004-07-29 | カディラ ヘルスケア リミティド | クロピドグレルの製造方法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2530247B1 (fr) | 1982-07-13 | 1986-05-16 | Sanofi Sa | Nouveaux derives de la thieno (3, 2-c) pyridine, leur procede de preparation et leur application therapeutique |
| HU222283B1 (hu) * | 1997-05-13 | 2003-05-28 | Sanofi-Synthelabo | Eljárás tieno[3,2-c]piridin-származékok előállítására |
-
2001
- 2001-01-24 IN IN84MU2001 patent/IN191030B/en unknown
- 2001-10-22 US US10/054,101 patent/US6635763B2/en not_active Expired - Lifetime
-
2002
- 2002-01-21 KR KR1020037009826A patent/KR100632748B1/ko not_active Expired - Fee Related
- 2002-01-21 PT PT02710298T patent/PT1353928E/pt unknown
-
2003
- 2003-06-24 ZA ZA200304895A patent/ZA200304895B/en unknown
-
2008
- 2008-07-09 JP JP2008179540A patent/JP2009029805A/ja not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63203684A (ja) * | 1987-02-17 | 1988-08-23 | サノフイ | 右旋性α−５−（４，５，６，７−テトラヒドロ［３，２−ｃ］チエノピリジル）−（２−クロロフェニル）酢酸メチル、その製法および医薬 |
| JP2004522744A (ja) * | 2001-01-24 | 2004-07-29 | カディラ ヘルスケア リミティド | クロピドグレルの製造方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200304895B (en) | 2004-05-12 |
| IN191030B (es) | 2003-09-13 |
| PT1353928E (pt) | 2007-03-30 |
| KR100632748B1 (ko) | 2006-10-11 |
| US20020177712A1 (en) | 2002-11-28 |
| KR20030081398A (ko) | 2003-10-17 |
| US6635763B2 (en) | 2003-10-21 |
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